The relationship between non-steroidal anti-inflammatory drug (NSAID) consumption and breast cancer has been repeatedly studied, although the results remain controversial. Most case-control studies reported that NSAID consumption protected against breast cancer, while most cohort studies did not find this effect.
Trang 1R E S E A R C H A R T I C L E Open Access
Use of non-steroidal anti-inflammatory
drugs and risk of breast cancer: The
Spanish Multi-Case-control (MCC) study
Trinidad Dierssen-Sotos1,2*, Inés Gómez-Acebo1,2, María de Pedro3, Beatriz Pérez-Gómez1,4,5, Sonia Servitja6,7, Víctor Moreno1,8, Pilar Amiano1,9, Tania Fernandez-Villa10,11, Aurelio Barricarte12,13, Adonina Tardon1,14,
Marian Diaz-Santos15,16, Rosana Peiro-Perez1,17, Rafael Marcos-Gragera18, Virginia Lope1,4,5,
Esther Gracia-Lavedan1,19,20, M Henar Alonso1,8, Maria Jesus Michelena-Echeveste21, Andrés Garcia-Palomo22, Marcela Guevara1,12,13, Gemma Castaño-Vinyals1,19,20,23, Nuria Aragonés1,4,5, Manolis Kogevinas1,19,20,
Marina Pollán1,4,5and Javier Llorca1,2
Abstract
Background: The relationship between non-steroidal anti-inflammatory drug (NSAID) consumption and breast cancer has been repeatedly studied, although the results remain controversial Most case-control studies reported that NSAID consumption protected against breast cancer, while most cohort studies did not find this effect Most studies have dealt with NSAIDs as a whole group or with specific drugs, such aspirin, ibuprofen, or others, but not with NSAID subgroups according to the Anatomical Therapeutic Chemical Classification System; moreover, scarce attention has been paid to their effect on different tumor categories (i.e.: ductal/non-ductal, stage at diagnosis or presence of hormonal receptors)
Methods: In this case-control study, we report the NSAID– breast cancer relationship in 1736 breast cancer cases and 1895 healthy controls; results are reported stratifying by the women’s characteristics (i.e.: menopausal status or body mass index category) and by tumor characteristics
Results: In our study, NSAID use was associated with a 24 % reduction in breast cancer risk (Odds ratio [OR] = 0.76;
95 % Confidence Interval [CI]: 0.64–0.89), and similar results were found for acetic acid derivatives, propionic acid derivatives and COXIBs, but not for aspirin Similar results were found in postmenopausal and premenopausal women NSAID consumption also protected against hormone + or HER2+ cancers, but not against triple negative breast cancers The COX-2 selectivity showed an inverse association with breast cancer (i.e OR < 1), except in advanced clinical stage and triple negative cancers
Conclusion: Most NSAIDs, but not aspirin, showed an inverse association against breast cancer; this effect seems to
be restricted to hormone + or HER2+ cancers
Keywords: Breast cancer, Non-steroidal anti-inflammatory drug, Hormone receptor positive breast cancer, HER2 positive breast cancer, Triple negative breast cancer
* Correspondence: dierssent@unican.es
1 CIBER Epidemiologia y Salud Publica (CIBERESP), Madrid, Spain
2 University of Cantabria – IDIVAL, Santander, Spain
Full list of author information is available at the end of the article
© 2016 The Author(s) Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver
Trang 2The cyclooxygenase-prostaglandin inflammation pathway
has been shown to play a relevant role in carcinogenesis,
mainly via inhibition of the cyclooxigenase-2 (COX-2)
iso-form [1] Experimental studies have demonstrated that
COX-2 blockade inhibits breast tumor formation in mice,
while its overexpression has the opposite effect [2]
There-fore, consumption of non-steroidal anti-inflammatory
drugs (NSAIDs) is expected to be protective for cancer
development
Regarding breast cancer, results from epidemiological
studies are inconsistent: cohort studies have reported
very modest protective effects or no effect at all [3–5],
while case-control studies have usually reported
moder-ate protective effects [6–8] Several meta-analyses have
been conducted; combination of results is, however,
complex because of differences in reporting of timing
and dosing of NSAIDs in the studies The most recent
meta-analysis reported a 20 % protective effect of
NSAID especially aspirin and COX-2 inhibitors against
breast cancer, which seems to be restricted to estrogen
receptors + (ER+) or progesterone receptors + (PR+)
tu-mors [9]
The number of epidemiological studies reporting
re-sults about the COX-2 inhibitors’ effect on breast cancer
or about NSAIDs’ effect on different types of breast
can-cer (i.e.: ER+, PR+, Human epidermal growth factor
re-ceptor [HER2] +, triple negative) is still small and
further studies are needed in order to clarify the specific
effect of NSAID groups on different types of breast
can-cer [8, 10–12] In order to further investigate this issue,
we report the results from a large case-control study
performed in Spain
Methods
Study design and population
The Multi Case-control (MCC-Spain) study is a
population-based case-control study of common tumors
in Spain and has been described elsewhere [13] It has
been carried out in 12 Spanish provinces The
recruit-ment included incident cases of colorectal, breast,
leukemia diagnosed between September 1st, 2008 and
December 31st, 2013, aged between 20 and 85 years old,
and resident within the influence area of the hospital at
least 6 months prior to recruitment Cases were identified
through active search that included periodical visits to the
collaborating hospital departments (i.e gynecology,
oncol-ogy, general surgery, radiotherapy, and pathology
depart-ments), but only histologically confirmed incident cases of
breast cancer (C50, D05.1, D05.7) with no prior history of
the disease were included in this study Ten out of 12
provinces recruited breast cancer cases and controls
Con-trols were selected from the general population according
to age and sex distribution of the cases included in the study In this paper, 1736 cases of breast cancer (ICD-10: C50, D05) in women and 1909 frequency-matched con-trols were considered
Response rates were 71 % for breast cancer and 72 % for controls, with no differences in the main socio-demographic variables among those who participated and those who refused to participate The Ethics Committees
of participating hospitals approved the study protocols, and participants provided written informed consent at the time of enrollment
Data collection
Participants were interviewed face-to-face by trained in-terviewers with a comprehensive epidemiological ques-tionnaire that assessed socio-demographic information, personal and family history of cancer, anthropometric data, smoking habits, occupation, physical activity, water consumption, reproductive and medical history and medication/drugs use, family history, sun exposure, sleep habits, use of hygiene products and cosmetics, signs and symptoms Diet was assessed with the use of a validated semi-quantitative Spanish Food Frequency Question-naire (FFQ), which was modified to include regional products The FFQ included 140 food items, and assessed usual dietary intake during the previous year Participant’s weight was recorded by self-report, as es-timated one year before diagnosis for cases and for con-trols Body mass index (BMI) was estimated from self-reported weight and height 1 year before the diagnosis for cases and 1 year prior to the interview for controls Similar estimates provided total energy consumption Physical activity was recorded for all jobs and also recre-ational physical exercise
Detailed information was obtained on past medical conditions and the corresponding medications used Par-ticipants were asked about past medical history of dia-betes mellitus, high blood pressure, high levels of cholesterol and triglycerides, heart attack, embolism, other cardiovascular diseases, degenerative osteoarthritis, arthritis, migraine or cephalalgia, gout, ulcerative colitis, Crohn’s disease, renal calculus (nephrolithiasis or cysto-lithiasis), chronic obstructive pulmonary disease, asthma, bronchitis, irritable bowel syndrome, anemia, diverticu-litis, celiac disease and cancer The age at onset, the dates of diagnosis or occurrence and the type of treat-ment received for each condition was also registered
Drug use assessment
Drug use was recorded by indication For each drug, the brand name, dose and duration of exposure were recorded
to identify patients with regular drug consumption (“no and occasionally” versus “yes”) and the duration
of consumption The drugs were coded following the
Trang 3Anatomical Therapeutic Chemical Classification
Sys-tem (ATC codes) to define groups with similar
mecha-nisms of action [14] To be sure that participants
report all drugs, a general question about the use of
NSAIDs was included in order to add information that
was not provided before
All drugs indicated for the treatment of inflammatory
diseases were considered The main ATC code included
in the present analysis are codes B01AC06 and
N02BA01 (Aspirin) and code M01 (Antiinflammatory
and antirheumatic drugs) Data were also analyzed for
subgroups with codes M01AA (Butilpirazolidins),
M01AB (acetic acid derivatives; for instance, diclofenac,
ketorolac), M01AC (Oxicams), M01AE (propionic acid
derivatives; for instance ibuprofen, naproxen), M01AH
(Coxibs; for instance, celecoxib), M01AX (other
NSAIDs) and their combinations Finally, as cox2
inhib-ition has been suggested as the putative mechanisms for
NSAID protective effect on breast cancer, we performed
a subgroup analysis according to level of
COX-selectivity In this way, NSAIDs were grouped in
cox1-selective/cox2-selective according to their log [IC80 ratio
(WHMA COX-2/COX-1)] [15] NSAIDs with negative
log (IC80 ratio) were considered cox2-selective (for
in-stance, meloxicam, diclofenac, sulindac, piroxicam,
niflumic acid), while NSAIDs with positive log (IC80
ra-tio) were considered cox1-selective (for instance:
ibu-profen, naproxen, indomethacin, ketoibu-profen, ketorolac)
As the putative protective mechanism of aspirin is not
via cox-2 inhibition, we retained aspirin as an
independ-ent group
Statistical methods
Unconditional logistic regression was used to assess the
association between treatment of NSAID use and breast
cancer, adjusting for age, recruitment area, education
level, tobacco smoking history, BMI, family history of
breast cancer, number of deliveries, age at first delivery,
menarche age, and menopausal status Stratified models
were developed according to menopausal status and
BMI [<25/≥25 kg/m2
] The association between tumor characteristics (clinical stage, ductal/non-ductal cancer,
hormone receptors, HER2 receptors and triple negative
breast cancer) and NSAID consumption was studied
using multinomial logistic regression Results are
re-ported as odds ratios (OR) with 95 % confidence
inter-vals (CI) All reportedp-values are two-tailed Statistical
analysis was carried out using the package Stata 12/SE
(StataCorp, College Station, Tx, US)
Results
A description of the 1736 cases and 1909 controls
in-cluded in this study is provided in Table 1 Significant
differences are observed between cases and controls for
several well known risk factors for breast cancer, includ-ing family history of breast cancer, age at menarche, and tobacco smoking Clinical-pathological characteris-tics of the breast cancers are reported in Table 2; ductal cancer accounts for 85 % of cases; two out of three breast cancers were diagnosed at stage I or II; more than 70 % of cancers were estrogen receptors +, 14 % were HER2 receptors + and only 6 % were triple nega-tive breast cancers Results on NSAID consumption – breast cancer association are reported here for con-sumption of any NSAID, aspirin, acetic acid derivatives, propionic acid derivatives, COX-2 inhibitors (COXIBs), and other NSAIDs We do not report results on butil-pirazolidins because of the small number of women ex-posed to this group
NSAID consumption and breast cancer according to women’s characteristics
Results on the relationship between NSAID consumption and breast cancer overall and by menopausal status and BMI, according to women’s characteristics are reported in Tables 3 and 4 for duration of use, and Additional file 1: Table S1 according to COX2/COX1 selectivity NSAIDs
as a global group protected against breast cancer (OR = 0.76; 95 % CI: 0.64–0.89); a protective effect was also found for acetic acid derivatives, propionic acid deriva-tives and COXIBs, but not for aspirin, although COXIB results were based on small numbers of exposed cases and controls, hampering further analysis of their effect
in specific subgroups of women When stratifying for menopausal status, all NSAIDs, acetic acid derivatives, propionic acid derivatives and COXIBs showed a pro-tective effect in postmenopausal women; ORs in post-menopausal women were similar or slightly lower to those in premenopausal women P values for NSAID– menopausal interaction status were higher than 0.10 (p values not shown) The protective effect of any NSAID was independent of BMI; however, the effect varied in subgroups: acetic acid derivatives were protective in women with BMI < 25 kg/m2 (OR = 0.54; 95 % CI: 0.31–0.93) but not in overweight or obese women, while propionic acid derivatives (OR = 0.78; 95 % CI: 0.61–1.00) protected only in the latter group; p values for BMI – NSAID interaction were non-significant Table 4 reports the results according to the duration of NSAID consumption (never/less than 5 years/more than 5 years) It shows that most of the results described
in the paragraph above had consistent dose-effect relation-ship: the longer the consumption, the lower the odds ratio Additional file 1: Table S1 shows a greater protective effect
of COX-2 both globally (OR = 0.66; 95 % CI: 0.48–0.90 for COX-2 vs OR = 0.81; 95 % CI: 0.67–0.98) for COX-1 se-lectivity) and in postmenopausal women and in women with BMI <25 kg/m2
Trang 4NSAID consumption and breast cancer according to
tumor characteristics
Results for subgroups of breast cancer are reported in
Tables 5 and 6 (for duration of use) and Additional file
2: Table S2 (according to COX2/COX1 selectivity) The
protective effect of any NSAID seemed similar in early
or late clinical stages (OR = 0.80; 95 % CI: 0.66–0.97 in stages 1–2; OR = 0.74; 95 % CI: 0.51–1.06 in stages 3–4), but no specific NSAID group reached statistically signifi-cant effect Consumption of any NSAID, acetic acid de-rivatives and propionic acid dede-rivatives was protective for ductal cancer (OR for any NSAID = 0.70; 95 % CI:
Table 1 Main characteristics of cases and controls from the study population
First-degree relative 256 (14.9) 166 (8.7) Second-degree relative 174 (10.1) 106 (5.8) <0.001 Educational level, n (%) Less than primary school 268 (15.4) 327 (17.3)
Trang 50.58–0.84) but not for non-ductal cancer, although the p
value for heterogeneity was non-significant for NSAID
as a group or for any specific subgroup All NSAID
con-sumption was protective for hormone receptor + cancer
(i.e.: ER+ or PR+) (OR = 0.72; 95 % CI: 0.60–0.88) and
HER2+ cancers (OR = 0.63; 95 %: 0.45–0.88) Propionic
acid derivatives also showed this protective effect in
hor-mone + or HER2+ cancers, while acetic acid derivatives
showed a non-statistically significant effect (OR = 0.76;
95 % CI: 0.54–1.08 in hormone receptor + cancers and
OR = 0.67; 95 % CI: 0.36–1.24 in HER2 receptor +
can-cers) Neither consumption of NSAID in general nor any
specific NSAID subgroup showed a protective effect in
triple negative breast cancers
When studying the effect of length of consumption
(Table 6), most associations reported above were at least
as strong in patients with more than 5 years of
consump-tion as in patients with less than 5 years
Finally, regarding the COX-selectivity of the NSAID
(Additional file 2: Table S2), the COX-2 selectivity showed
an inverse association with breast cancer (i.e OR < 1),
ex-cept in advanced clinical stage and triple negative cancers
Discussion
In this large case-control study, NSAID use was associated
with a 24 % reduction in breast cancer risk An inverse
association were observed specifically for acetic acid de-rivative and propionic acid dede-rivative use, but not for as-pirin consumption There is a trend towards a stronger protective effect of NSAID in postmenopausal women, ductal cancer, and hormone receptor or HER2 receptor positive tumors This protective effect was less pro-nounced in premenopausal women, non-ductal cancer, or triple negative cancer, although the small number of cases with triple negative cancer makes it difficult to reach de-finitive conclusions
Regarding NSAID effect overall, our results are coher-ent with those reported in 10 out of 16 case-control studies [6–8, 16–22], while the remaining six studies did not show any effect [23–28] Results from 13 cohort studies hardly support any NSAID effect on breast can-cer risk; only four reported protective effects [3, 4, 29, 30], seven did not find any association [5, 31–35], and three reported an increase in breast cancer risk [36–38] Consequently, a recent meta-analysis [9] showed a sig-nificant protective odds ratio (OR = 0.82) when combin-ing case-control studies, but a non-significant relative risk (RR = 0.92) in cohort studies Most studies, however, did not report stratified results
Some studies have analyzed the effect of aspirin, ibu-profen or non-aspirin NSAIDs, reporting similar results
to those presented for NSAIDs in general (i.e.: protective effect in case-control studies; no effect in cohort studies) [9] Scarce attention has been paid, however, to the effect associated with different pharmacological subgroups According to our results, acetic acid derivatives, propio-nic acid derivatives and COX-2 inhibitors have a pro-tective effect against breast cancer incidence, while aspirin has no effect at all The absence of a significant effect of aspirin is puzzling since prior investigations have noted not only preventive effects but also thera-peutic effects of aspirin against breast cancer In this re-gard, aspirin consumption could be underreported in our study due to its common over-the-counter usage; as this possible underreporting would affect both cases and controls in a similar way, it would eventually lead to a bias towards the null, which would justify a negative re-sult This phenomenon is not to be expected in other NSAIDs as their usual consumption is by prescription The public health implications of the reduction in breast cancer risk when taking acetic acid and propionic acid derivatives should be highlighted as these groups account for about 80 % of NSAID consumption in the Spanish population A note of caution should be remarked on aspirin results; the percentage of people declaring aspirin consumption seems low, which could
be due to a reporting bias Study participants were asked
to report the diseases they were suffering from and the drugs they had been taking for treating them and we have also asked whether they were taking any other
Table 2 Clinical and pathological characteristics of breast cancers
Pathology
Clinical stage
Inmunohistochemistry
Trang 6NSAID not reported before It is possible that some
people might not consider aspirin to be a drug, so failing
to declare its usage
Most studies did not analyze NSAID effect on several
types of breast cancer According to our results, the
in-verse association of NSAID with breast cancer is more
pronounced in postmenopausal cancers, ductal cancer,
and hormone receptor or HER2 receptor positive tumors
This effect increases in women treated with COX-2
in-hibitors, especially in early clinical stage,
postmeno-pausal cancers and receptor positive tumors The
putative pathway for the NSAID protective effect is via
COX inhibition High levels of prostaglandins, derived
from the activation of the COX/prostaglandin pathway,
contribute to carcinogenesis in various ways (increase in mitogenesis, mutagenesis, angiogenesis, metastasis forma-tion, inhibition of apoptosis, and immunosuppression) [38–40] Constitutive expression of the COX-2 gene and sustained biosynthesis of PGE2seem to be associated with the initiation and promotion of breast carcinogenesis [41]
In a prospective study, COX-2 expression in biopsy speci-mens from women with atypical breast hyperplasia was a significant predictor of breast cancer risk [42]; COX-2 overexpression, therefore, seems to constitute an early event in breast carcinogenesis, which makes COX-2 a potential cancer biomarker and a key target for breast cancer prevention [43] Unfortunately, cardiovascular tox-icity attributed to COX-2 inhibitors has partially decreased
Table 3 Relationship between NSAID consumption and breast cancer according to women’s characteristics
Population NSAID Unexposed controls/cases (n) Exposed controls/Cases (n) OR (95 % CI) p
OR Odds ratio adjusted for age, recruitment area, education level, tobacco smoking history, BMI family history of breast cancer, number of deliveries, age at first delivery, menarche age, and menopausal status CI confidence interval
Trang 7their usefulness, whatever their effect on breast cancer
might be
On the other hand, COX inhibition would reduce
aro-matase activity [44] Peripheral aromatization of fatty acids
is known to be largely responsible for estrogen production
in postmenopausal women –in whom adipose tissue
rep-resents an important local source of estrogen-; therefore,
regulation of aromatase synthesis in the breast could be
particularly important in postmenopausal breast cancer
[45] Reducing aromatase activity via COX inhibition could
also explain, at least partially, the decrease in breast cancer
incidence linked to NSAID use [8], since COX inhibition
would reduce estrogen concentration in the breast,
restricting the growth of estrogen-dependent tumors
This study has several limitations First, NSAID
con-sumption was self-reported, which could introduce a
re-call bias For a rere-call bias to be responsible for the
protective effects reported here, the bias would have to
be differential in cases and controls, with controls re-membering their previous NSAID consumption better; this seems counterintuitive as one would expect cases to
be more motivated for remembering their previous ex-posures In addition, if cases are less prone to report their NSAID usage, the same bias would be expected in all NSAID groups and in each stratum analyzed; how-ever, our results were different according to the type of NSAID, which seems to contradict such a bias More-over, in order to minimize a differential recall bias, inter-viewers were blinded to the case-control status of the participants Second, although our intention was to rec-ord data on aspirin dosage, most patients did not pro-vide sufficiently detailed data on dosages of aspirin or other NSAID use This fact prevents us from analyzing the dose-effect relationship Third, we have adjusted for the usual confounders but residual confounding cannot
be ruled out Finally, any case-control study could be
Table 4 Relationship between length of non-steroideal anti-inflammatory drug consumption and breast cancer, according to women’s characteristics
Controls/cases (n) Controls/cases (n) OR (95 % CI) Controls/cases (n) OR (95 % CI) All women NSAID (all) 1171/1111 484/445 0.81 (0.67 –0.98) 255/180 0.64 (0.50 –0.83)
Acetic acid derivatives 1754/1620 113/86 0.75 (0.53 –1.06) 43/30 0.75 (0.42 –1.32) Propionic acid derivatives 1351/1232 380/364 0.86 (0.71 –1.06) 179/140 0.73 (0.55 –0.97)
-Premenopausal NSAID (all) 361/415 162/187 0.82 (0.59 –1.13) 105/100 0.78 (0.52 –1.17)
-Acetic acid derivatives 600/664 21/27 0.68 (0.35 –1.34) 7/11 1.02 (0.31 –3.32) Propionic acid derivatives 392/461 146/167 0.85 (0.61 –1.19) 90/84 0.81 (0.52 –1.25)
-Postmenopausal NSAID (all) 805/696 312/258 0.77 (0.61 –0.98) 150/80 0.53 (0.38 –0.75)
Acetic acid derivatives 1143/956 88/59 0.76 (0.50 –1.15) 36/19 0.61 (0.31 –1.20) Propionic acid derivatives 954/781 224/197 0.84 (0.64 –1.09) 89/56 0.64 (0.43 –0.95)
-Acetic acid derivatives 883/783 44/22 0.40 (0.20 –0.77) 15/14 1.16 (0.42 –3.15) Propionic acid derivatives 656/575 191/163 0.89 (0.66 –1.21) 95/81 0.80 (0.52 –1.22)
Acetic acid derivatives 871/837 69/64 0.94 (0.61 –1.44) 28/16 0.54 (0.27 –1.10) Propionic acid derivatives 695/657 189/201 0.85 (0.64 –1.12) 84/59 0.64 (0.43 –0.95)
-OR Odds ratio adjusted for age, recruitment area, education level, tobacco smoking history, BMI family history of breast cancer, number of deliveries, age at first delivery, menarche age, and menopausal status CI confidence interval
Trang 8Table 5 Relationship between consumption of non-steroideal anti-inflammatory drugs and breast cancer, according to tumor characteristics
controls/cases (n)
Exposed controls/cases (n)
OR (95 % CI) P
Acetic acid derivatives 1753/1025 156/74 0.75 (0.54 –1.06) 0.11 Propionic acid derivatives 1350/770 559/329 0.90 (0.74 –1.11) 0.33
Acetic acid derivatives 1753/190 156/14 0.99 (0.53 –1.83) 0.97 Propionic acid derivatives 1350/147 559/57 0.84 (0.57 –1.24) 0.39
Acetic acid derivatives 1753/1204 156/85 0.76 (0.55 –1.06) 0.11 Propionic acid derivatives 1350/918 559/371 0.78 (0.64 –0.95) 0.01
Non-ductal cancer NSAID (all) 1170/151 739/83 0.82 (0.58 –1.15) 0.25
Acetic acid derivatives 1753/219 156/15 0.85 (0.46 –1.58) 0.61 Propionic acid derivatives 1350/166 559/68 0.91 (0.63 –1.31) 0.60
-Inmunohistochemistry Hormone + NSAID (all) 1170/727 739/390 0.72 (0.60 –0.88) <0.001
Acetic acid derivatives 1753/1044 156/73 0.76 (0.54 –1.08) 0.12 Propionic acid derivatives 1350/805 559/312 0.80 (0.65 –0.98) 0.03
Acetic acid derivatives 1753/238 156/17 0.67 (0.36 –1.24) 0.20 Propionic acid derivatives 1350/188 559/67 0.66 (0.46 –0.95) 0.03
-Triple negative breast cancer
Acetic acid derivatives 1753/147 156/10 0.86 (0.41 –1.79) 0.68 Propionic acid derivatives 1350/103 559/54 0.99 (0.64 –1.52) 0.95
-OR Odds ratio adjusted for age, recruitment area, education level, tobacco smoking history, BMI family history of breast cancer, number of deliveries, age at first delivery, menarche age, and menopausal status CI confidence interval
Trang 9affected by a selection bias Our study is population
based, as controls have been selected from the same
residence area as cases; the small differences in case and
control educational levels suggest that the selection has
been adequately carried out Moreover, the high re-sponse rates obtained in this study (71 % for breast can-cer cases and 72 % for controls, respectively) minimize the possibility of occurrence of such bias
Table 6 Relationship between length of non-steroideal anti-inflammatory drug consumption and breast cancer, according to tumor characteristics
Controls/cases (n)
Controls/cases (n)
OR (95 % CI) Controls/cases
(n)
OR (95 % CI) Clinical stage 1 –2 NSAID (all) 1171/695 484/281 0.85 (0.69 –1.06) 255/123 0.69 (0.52 –0.92)
Aspirin 1808/1047 79/44 1.01 (0.65 –1.58) 23/8 0.74 (0.31 –1.73) Acetic acid
derivatives
1754/1025 113/53 0.79 (0.53 –1.17) 43/21 0.73 (0.38 –1.42) Propionic acid derivatives 1351/770 380/234 0.93 (0.73 –1.17) 179/95 0.78 (0.57 –1.08)
-3 –4 NSAID (all) 1171/136 484/54 0.85 (0.57 –1.27) 255/14 0.46 (0.24 –0.88)
-Acetic acid derivatives 1754/190 113/12 1.08 (0.54 –2.17) 43/2 -Propionic acid derivatives 1351/147 380/45 0.91 (0.59 –1.40) 179/12 0.54 (0.27 –1.09)
-Pathology Ductal cancer NSAID (all) 1171/835 484/324 0.74 (0.60 –0.91) 255/130 0.60 (0.45 –0.79)
Aspirin 1808/1225 79/56 1.09 (0.72 –1.66) 23/8 0.60 (0.26 –1.41) Acetic acid derivatives 1754/1204 113/64 0.78 (0.53 –1.14) 43/21 0.68 (0.36 –1.30) Propionic acid derivatives 1351/918 380/270 0.81 (0.65 –1.02) 179/101 0.68 (0.49 –0.94) NSAID others 1862/1259 33/28 1.42 (0.77 –2.67) 15/2
Non-ductal cancer NSAID (all) 1171/151 484/50 0.78 (0.53 –1.15) 255/33 0.90 (0.55 –1.48)
-Acetic acid derivatives 1754/219 113/11 0.92 (0.45 –1.87) 43/4 -Propionic acid derivatives 1351/166 380/40 0.79 (0.51 –1.22) 179/28 1.15 (0.67 –1.96)
-
Inmunohisto-chemistry
Hormone + NSAID (all) 1171/727 484/267 0.74 (0.60 –0.92) 256/123 0.69 (0.52 –0.92)
Aspirin 1808/1069 79/38 0.85 (0.54 –1.36) 23/10 0.79 (0.36 –1.75) Acetic acid
derivatives
1754/1044 113/50 0.69 (0.46 –1.04) 43/23 0.94 (0.51 –1.75) Propionic acid derivatives 1351/805 380/221 0.82 (0.65 –1.04) 179/91 0.76 (0.55 –1.05)
-HER2 +/Hormone- NSAID (all) 1171/172 484/61 0.70 (0.48 –1.01) 255/22 0.49 (0.28 –0.87)
-Acetic acid derivatives 1754/238 113/16 1.02 (0.29 –3.60) 43/1 -Propionic acid derivatives 1351/188 380/47 0.66 (0.43 –0.99) 179/20 0.61 (0.33 –1.12)
-Triple negative
breast cancer
NSAID (all) 1171/94 484/49 0.94 (0.60 –1.48) 255/14 0.60 (0.30 –1.17)
-Acetic acid derivatives 1754/144 113/8 0.85 (0.36 –2.01) 43/2 -Propionic acid derivatives 1351/103 380/42 1.04 (0.64 –1.68) 179/12 0.68 (0.32 –1.43)
-OR odds ratio adjusted for age, recruitment area, education level, tobacco smoking history, BMI family history of breast cancer, number of deliveries, age at first delivery, menarche age, and menopausal status CI: confidence interval
Trang 10Summarizing, although there is increasing evidence for a
protective effect of NSAID against breast cancer risk,
our results indicate that this effect is more pronounced
in postmenopausal women and in
estrogen/progester-one + receptor or HER2+ cancers As this effect seems
to be moderate, concerns remain about whether NSAID
may play a role in chemoprevention or just indicate a
pathway for identifying further more specific drugs that
could be used for breast cancer chemoprevention in high
risk women
Additional files
Additional file 1: Table S1 Relationship between NSAID consumption
and breast cancer according to COX2/COX1 selectivity and women ’s
characteristics (DOC 34 kb)
Additional file 2: Table S2 Relationship between NSAID consumption
and breast cancer according to COX2/COX1 selectivity and tumor
characteristics (DOC 39 kb)
Acknowledgements
Not applicable.
Funding
The study was partially funded by the “Accion Transversal del Cancer”
approved by the Spanish Council of Ministers on the 11th October 2007, by
the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PI09/
00773-Cantabria, PI09/01286-León, PI09/01903-Valencia, PI09/02078-Huelva,
PI09/01662-Granada, PI11/01403, PI11/01889-FEDER, PI11/00226, PI11/01810,
PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150,
PI14/01219, PI15/00069), by the Fundación Marqués de Valdecilla (API 10/09),
by the ICGC International Cancer Genome Consortium CLL (The ICGC
CLL-Genome Project is funded by Spanish Ministerio de Economía y
Competitividad (MINECO) through the Instituto de Salud Carlos III (ISCIII) and
Red Temática de Investigación del Cáncer (RTICC) del ISCIII (RD12/0036/0036)),
by the Junta de Castilla y León (LE22A10-2), by the Consejería de Salud of the
Junta de Andalucía (2009-S0143), by the Conselleria de Sanitat of the Generalitat
Valenciana (AP_061/10), by the Recercaixa (2010ACUP 00310), by the Regional
Government of the Basque Country, by the European Commission grants
FOOD-CT-2006-036224-HIWATE, by the Spanish Association Against Cancer
(AECC) Scientific Foundation and by the Catalan Government DURSI grant
2009SGR1489.
Availability of data and materials
The datasets generated during and/or analysed during the current study are
not publicly available because the informed consent signed by all
participants explicitly excludes the authorization for sharing data.
Authors ’ contributions
TDS, IGA, MdP and JL contributed substantially to the conception, design
and acquisition of data TDS, IGA and JL contributed to the analysis and
interpretation of the data TDS, IGA, MP and JL contributed to devising the
draft of the article The remaining authors (BPG, SS, VM, PA, TFV, AB, AT, MDS,
RPP, RMG, VL, EGL, MHA, MJME, MG, GCV, NA, MK and MP) participated in
the patients ’ recruitment, acquisition of data and critical revision of the
manuscript All authors approved the final version to be published.
Authors ’ information
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate This study was approved by the corresponding ethics committee of each area (Comité ético de investigación clínica de Asturias, Barcelona, Cantabria, Girona, Gipuzkoa, Huelva, León, Madrid, Navarra and Valencia) and informed written consent was obtained from parents The MCC-Spain study also followed the Declaration of Helsinki and the Spanish Personal Data Protection Act of
1999 Informed consent was obtained from all individual participants included
in the study All procedures were performed with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards Author details
1 CIBER Epidemiologia y Salud Publica (CIBERESP), Madrid, Spain 2 University
of Cantabria – IDIVAL, Santander, Spain 3 Department of Obstetrics and Gynecology, Nuevo Belén University Hospital, Madrid, Spain 4 Cancer and Environmental Epidemiology Unit, National Center for Epidemiology, Carlos III Institute of Health, Madrid, Spain 5 Cancer Epidemiology Research Group, Oncology and Hematology Area, IIS Puerta de Hierro (IDIPHIM), Madrid, Spain 6 Servei d ’Oncologia Mèdica, Hospital del Mar, Barcelona, Spain.
7
Cancer Research Program IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain 8 Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, and University of Barcelona, Barcelona, Spain.
9 Public Health Division of Gipuzkoa, Biodonostia Research Institute, San Sebastian, Spain.10Área de Medicina Preventiva y Salud Pública, Departamento de Ciencias Biomédicas, Universidad de León, León, España.
11 Grupo de Investigación en Interacciones Gen-Ambiente y Salud (GIIGAS), Universidad de León, León, España 12 Navarra Public Health Institute, Pamplona, Spain.13Navarra Institute for Health Research (IdiSNA), Pamplona, Spain 14 IUOPA, Universidad de Oviedo, Oviedo, Spain 15 Universidad de Huelva, Huelva, Spain 16 Centro de Investigación en Salud y Medio Ambiente (CYSMA), Huelva, Spain 17 Area de Cáncer y Salud Pública, Fundación FISABIO- Salud Pública, Valencia, Spain.18Epidemiology Unit and Girona Cancer Registry, Oncology Coordination Plan, Department of Health, Autonomous Government of Catalonia and Descriptive Epidemiology, Genetics and Cancer Prevention Group [Girona Biomedical Research Institute (IdIBGi)], Catalan Institute of Oncology, Girona, Spain.19Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain 20 Universitat Pompeu Fabra (UPF), Barcelona, Spain 21 Onkologikoa- Oncology Institute Gipuzkoa, San Sebastian, Spain 22 Sección de Oncología, Complejo Asistencial Universitario de León, León, Spain.23IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
Received: 1 December 2015 Accepted: 9 August 2016
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